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Complement

Complement. J . Ochotná. Complement. humoral component of nonspecific immunity helps remove microorganisms and own altered cells (apoptotic cells) complement proteins are synthesized in the liver, less by tissue macrophages and fibroblasts. Complement.

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Complement

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  1. Complement J. Ochotná

  2. Complement • humoralcomponentofnonspecificimmunity • helps remove microorganisms and own altered cells (apoptotic cells) • complementproteins are synthesized in the liver, less by tissuemacrophagesandfibroblasts

  3. Complement • systemofabout 30 serumandmembraneproteins • complementcomponents are present in serumin inactiveform • complementactivationiscascadecharacter

  4. Riedemann N.C. Pathways of complement activation • Classical pathway • Alternative pathway • Lectin pathway

  5. Classical complement pathway • canbeinitiated by antibodiesIgG ( not by IgG4) andIgMor by pentraxins (CRP, SAP - acutephaseproteins) • afterbindingofantibodies to thebacteriasurface, Ab changesitsconformationandthancanbind C1 protein • https://www.youtube.com/watch?v=vbWYz9XDtLw

  6. Alternative complement pathway • C3 componentofcomplementrarelyspontaneouslybreaksinto C3b and C3a • C3bcancovalentlybind on thesurfaceof a particle (own cell, microorganism) orreactswithwater, therebyinactivates • https://www.youtube.com/watch?v=qga3Wn76d9w

  7. Lectin complement pathway • isinitiated by serummannosebindinglectin (MBL) • MBL binds to mannoseresidues on thesurfaceofsomemicrobes, afterthisbindingstartscleave C4 and C2 • thiswayissimilar to theclassicalpathway • https://www.youtube.com/watch?v=utQdPPeeTLQ

  8. Biological significance of complement • Opsonization (C3b, C4b) • Chemotaxis (C3a, C5a) • Osmotic lysis (MAC C5b-C9) • Anaphylatoxins (C3a, C4a, C5a)

  9. Complement activation and efector functions

  10. Efector functions of complement

  11. Complement regulation and protection of own cells • Activation of complement cascade is controlled by the plasma and membrane inhibitors. Anaphylatoxin inactivator DAF Protectin MCP

  12. Complement regulation • C1 inhibitor(C1-INH) – inhibits C1; ifmissing→ HAE • factor Iwithcofactors: MCP (membranecofactor protein), CR1,factor H – C3b, C4b cleavage • DAF (decay-accelerating protein)degradationof C3 and C5 convertase

  13. Complement regulation • factor S (vitronectin) – inhibitscomplex C5bC6 • CD 59(protectin) - preventsthepolymerizationof C9 • anaphylatoxininactivator(CPN)inactivatesanafylatoxins(C3a, C4a, C5a)

  14. Complement receptors • Bindfragmentsofcomplementcomponents • CR1 - on variouscells - promotes C3b, C4b decay - stimulatephagocytosis - erythrocyte transport ofimmunecomplexes • CR2 - on B lymphocytesand FDC - activationof B cells

  15. Complement receptors • CR3, CR4 - on phagocytes - participation in opsonization, adhesion Anaphylatoxinreceptors • C3aR, C5aR – receptorsforanaphylatoxins - mast cell activation

  16. Basophils and mast cells and their importance in immune responses

  17. Mast cells • Mucosal mast cells- in the mucous membranes of respiratory and gastrointestinal tract, produce histamine, serotonin, heparin, tryptase, leukotriene C4 ..., participate in parasitosis and allergy • Connective tissue mast cells– in parasitosis and allergy are not participating

  18. Mast cell functions • Defense againstparasiticinfections • In pathologicalcircumstances, responsiblefortheallergicreactions(immunopathologicalreaction type I) • Applyduringinflammation, in angiogenesis, in tissueremodeling

  19. Mast cell activation • cross-linkingofIgEreceptors(FcRI) • anafylatoxins (C3a, C4a, C5a) • TLR

  20. Mast cell activation by cross-linking of IgE Fc receptors • BindingofIgE to highaffinnityFc receptor forIgE (FcRI) • Bindingof multivalent antigen (multicellular parasite) to IgE • AggregationofseveralmoleculesofFcRI → activation

  21. Mast cell activation • Mast cell degranulate (cytoplasmicgranulesmergerswiththesurfacemembraneandreleasetheircontents) • Activationofarachidonicacidmetabolism (leukotriene C4, prostaglandin D2) • Start ofcytokinesproduction (TNF, TGF, IL-4, 5,6 ...)

  22. Secretory products of mast cells • Cytoplasmaticgranules:hydrolyticenzymes, histamine, heparin, chondroitin sulphate, serotonin Histamine - vasodilation, ↑ vascular permeability(erythema, edema, itching), bronchoconstriction, ↑ intestinalperistalsis, ↑mucussecretion in therespiratorytractand GIT (helpseliminatethe parasite) • Arachidonicacidmetabolites(leukotriene C4, prostaglandin D2) • Cytokines (TNF, TGF , IL-4, 5,6 ...) • https://www.youtube.com/watch?v=MoM5JY_EeRo

  23. Basophils • Differentiatefrommyeloidprecursor • Receptor equipment, contentofgranules, themechanismsofstimulationandfunctions are verysimilar to mast cells • Play a role in parasiticinfectionsandallergies • Basophilactivationmarkers: CD 63, (CD 203)

  24. Immune mechanisms of inflammation (Local and systemic reactions)

  25. Inflammation Is a protectivephysiological response leading to protectionagainstinfection in damagedsites, localizationofdamage, eliminationofnecroticcellsandtissuerepair.

  26. Causes of inflammation • Physicalinjury • Infection by pathogens • Damagecaused by chemicals • Cancer • Alergicdisease • Autoimmunedisease

  27. Local body's response to inflammationClassical signs- pain (dolor), fever (calor), redness (rubor), swelling (tumor)

  28. Inflammation • Thefirstsignalsforthedevelopmentofinflammatory response comefrommast cells, phagocytes, andthesubstancesreleasedfromdamagedcellsandcomponentsofextracellular matrix. • An antigen-specific mechanisms (T and B lymphocytes) are activated with longer duration of local inflammation.

  29. Inflammation

  30. Inflammation – local reaction • vasodilation, ↑ vascular permeability (histamine, serotonin, bradykinin, complementcomponents C3a, C5a, leukotrienes , prostaglandins, …) → rednes, swelling • ↑expressionofadhesionmoleculeson endothelia(TNF, IL-1) →leukocyte adhesion to the endothelium • influence oflocal nerve endings via prostaglandins → pain • increasedlocaltemperature(IL-1, IL-6, TNF, prostaglandins)

  31. Inflammation - systemic reaction • Leukocytosis • Fever (TNF, IL-1, IL-6, IFN) ↑ tissue metabolism↑ mobility of leukocytes↑ formation of IFN, cytokines, Ig↑ expression of Hsp • Acute phase proteins (IL-6, TNF, IL-1) CRP, SAP - opsonization and complement activation

  32. Inflammation - systemic reaction • Septicshock- themassivepenetrationofmicroorganismsintothebloodstream (TNF) • Anaphylacticshock- basophiland mast cellsactivationwithallergen (histamine)

  33. Tissue repair • eliminationofdamagedcellswithphagocytes • activationoffibroplasticmechanisms • activationofangiogenesis • regenerationandtissueremodeling • TGF 

  34. Antigens

  35. Antigen (immunogen) • substance which provokes specific immune response • usually proteins or polysaccharides (lipids and nucleic acids only in the combination with proteins or polysaccharides) • molecules > 5 kDa (optimal size of the antigen molecules is about 40 kDa)

  36. Hapten • smallmolecules, that are able to inducespecificimmune response onlyaftertheattachmentto themacromolecularcarrier • separatehaptens are not immunogenic • typicallydrugs (eg penicillinantibiotics, hydralazin)

  37. Epitope (antigenic determinant) • part of the antigen which is recognized by immune system (lymphocytes- BCR, TCR, Ig) • cross-reactive antigens - share one or more identical or similar epitopes

  38. Interaction antigen – antibody • Binding site of antibody (paratop) form non-covalent complexes with the corresponding part on antigen molecule (epitope) • the hydrogen bonds, electrostatic and hydrophobic interactions, van der Waals forces • antigen-antibody complex is reversible

  39. Antigen • endogenousantigens- autoantigens (selfAg) • exogenousantigens- foreignsubstancesfromtheenvironment • allergenisexoantigenthat in thesusceptibleindividualscan cause pathological (allergic) immune response

  40. Properties of antigen • immunogenicity proteins> carbohydrates> macromoleculecomplexes (glycoproteins, nucleoproteins, andglycolipids)> lipids • specificity

  41. Factors affecting immunogenicity • Physical:solubility - insoluble Ag more immunogenicmolecular weight - ideal 5-40 kDa • Chemical:structure - the number of determinantsdegradability - "ease" of uncovering the determinants in antigen presenting cells (APC cell) • Biological:biological heterogeneitygenetic and physiological disposition of the body

  42. Degree of foreignness • Autogeneic- antigensofthesameindividual • Syngeneic- antigensofgeneticallyidenticalindividuals (eg twins) • Allogeneic (alloantigens) - antigensgeneticallydifferentindividualsofthesame species • Xenogeneic (heterologous) - antigensderivedfromindividualsofdifferent species (eg monkeykidneytransplant man)

  43. Typesofantigensaccordingto antigen presentation • T- dependentantigens • T- independent antigens

  44. Thymus dependent antigens • more frequently, mostlyprotein Ag • forspecifichumoralimmune response to antigen isnecessaryassistanceof THlymphocytes(or response isn´t enougheffective) • assistanceisimplemented in theformofcytokinesproduced by THlymphocytes

  45. T-independent pathway T- independent antigens • can stimulate B cells directly • mainly bacterial polysaccharides, lipopolysaccharides and polymeric forms of proteins (e.g. Haemophilus, Str.pneumoniae)

  46. Superantigens • stimulate T cellspolyclonalyandmassively (massivecytokinerelease) • massiveactivationof T cellscan cause shock • e.g. bacterialtoxins (Staph.aureus, Str.pyogenes, Pseud.aeruginosa)

  47. Superantigens • Superantigens are proteins with 2 binding sites, one interacts with the epitope presented on all MHCgpII, second interacts with structures presented in many different TCR molecules

  48. Sequestered antigens • autoantigens, that are normally hidden to immune system and therefore unknow (e.g. brain, the lens of the eye , testes) • if they are "uncovered" by demage, exposed to the immune system, are recognized as foreign (one of the theories of autoimmune processes)

  49. Immunologically privileged sites • brain, eye, gonads • are protectedfrompotentiallydamaginginflammatoryimmuneresponses • thistissues are far lessrejected in allogeneictransplant (cornea) • thisprivilegedpositionis not absolute

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